1. Field of the Invention
The present invention relates to a method of producing enantiomer-enriched amino acids and amino-acid derivatives of the general formula (I) or acid addition salts thereof ##STR3## in which *=center of asymmetry
X=O or NH PA1 R.sup.1 =H, (C.sub.1 -C.sub.6) alkyl, benzyl or (C.sub.3 -C.sub.6) alkoxycarbonylmethyl and PA1 R.sup.2 =H or (C.sub.1 -C.sub.6) alkyl, which can be interrupted or substituted with heteroatoms such as N, P, O, S or Si, which heteroatoms can be substituted themselves singly or multiply with linear or branched (C.sub.1 -C.sub.3) alkyl, (C.sub.2 -C.sub.6) alkenyl, (C.sub.1 -C.sub.6) haloalkyl, halogen, aryl, such as naphthyl or phenyl, which can be substituted singly or multiply with (C.sub.1 -C.sub.3) alkyl, hydroxy, halogen or (C.sub.1 -C.sub.3) alkoxy, aralkyl such as 2-naphthylmethyl or benzyl or 1,1- or 1,2-phenethyl, which for its part can be substituted singly or multiply with (C.sub.1 -C.sub.3) alkyl, hydroxy, halogen or (C.sub.1 -C.sub.3) alkoxy, heteroaralkyl such as N-protected 3-indolylmethyl, and PA1 R.sup.3 signifies H or OH, PA1 X=O or NH PA1 R.sup.1 =H, (C.sub.1 -C.sub.6) alkyl, benzyl or (C.sub.3 -C.sub.6) alkoxycarbonylmethyl and PA1 R=H or (C.sub.1 -C.sub.6) alkyl, which can be interrupted or substituted with heteroatoms such as N, P, O, S or Si, which heteroatoms can be substituted themselves singly or multiply with (C.sub.1 -C.sub.3) alkyl, (C.sub.2 -C.sub.6) alkenyl, (C.sub.1 -C.sub.6) haloalkyl, halogen, aryl, such as naphthyl or phenyl, which can be substituted singly or multiply with (C.sub.1 -C.sub.3) alkyl, hydroxy, halogen or (C.sub.1 -C.sub.3) alkoxy, aralkyl such as 2-naphthylmethyl or benzyl or 1,1- or 1,2- phenethyl, which for its part can be substituted singly or multiply with (C.sub.1 -C.sub.3) alkyl, hydroxy, halogen or (C.sub.1 -C.sub.3) alkoxy, heteroaralkyl such as N-protected 3-indolylmethyl, and R.sup.3 signifies H or OH,
from enantiomer-enriched nitrons of the general formula (II) ##STR4## in which * and R.sup.1 have the significance indicated above.
2. Background Information
Enantiomer-enriched amino acids and amino-acid derivatives are important substances in the organic synthesis of peptides and peptide-mimetic substances which are used in drugs and biologically active substances. Thus, the optically active tert.-leucine methylamide which can be produced according to the method of the invention is required in the synthesis for producing a matrix metalloproteinase inhibitor which is currently being investigated in the clinical phase for the combating of tumors (J. Med. Chem. 1998, 41, 1209-1217).
WO 97/10203 teaches a method for the addition of nucleophiles onto nitrons of the general formula (II). However, the known method is based on the use of strong bases such as alkyl metal compounds. One is therefore limited to the use of dehydrated solvents and working under inert atmosphere protective gas as well as the exclusion of any traces of water during the reaction. Such methods are difficult to carry out on an industrial scale.
A method for the addition of radical compounds to derivatives of the general formula (II) is likewise mentioned in WO 97/10203. The reaction of the derivatives (II) with a carboxylic acid in the presence of a radical starter in various solvents under the exclusion of oxygen was described there. However, under the selected conditions .alpha.-substituted nitrons are recovered after the reaction without the actually desired asymmetry on the .alpha.-C atom of the amino-acid structural element.
According to Iwamura et al. (Bull. Chem. Soc. Jpn. 1970, 43, 856-860) 1,3 addition products or nitroxides or substituted nitrons are obtained in the reaction of nitrons with radicals. In certain instances the substituted nitroxide disproportionates in nitron and hydroxylamine (Iwamura et al., Bull. Chem. Soc. Jpn. 1967, 40, 703). The products were not isolated; however, this mechanism permits a yield of only a maximum of 50% of the desired compound. 50% of the product compounds accumulate as waste, which is considered from the industrial standpoint as a not very logical product variant.
All previously described method variants for the addition of compounds to nitrons of the formulas (II) (see WO 97/10203) have the disadvantages that they supply only moderate yields, especially in the case of bulky amino acids, and in some instances require a complicated conduction of the reaction (metallo-organic reagents, exclusion of water,e purification, etc.).